tbuckley/cabot-search huggingface dataset:
Reset of Inflammatory Priming of Joint Tissue and Reduction of the Severity of Arthritis Flares by Bromodomain Inhibition
Authors: Jasna Friščić, Christiane Reinwald, Martin Böttcher, Miranda Houtman, Maximilien Euler, Xi Chen, Kellie I. Walker, Philipp Kirchner, Honglin Zhu, Benjamin Wirth, Daniela Weidner, René Krüger, Vladimir Trajkovic, Arif B. Ekici, Kerstin Klein, Dimitrios Mougiakakos, Caroline Ospelt, Georg Schett, Markus H. Hoffmann
Journal: Arthritis & Rheumatology (2022)

Objective We have recently shown that priming of synovial fibroblasts (SFs) drives arthritis flares. Pathogenic priming of SFs is essentially mediated by epigenetic reprogramming. Bromodomain and extraterminal motif (BET) proteins translate epigenetic changes into transcription. Here, we used a BET inhibitor (I‐BET151) to target inflammatory tissue priming and to reduce flare severity in a murine experimental arthritis model. Methods BALB/c mice were treated by intraperitoneal injection or by local injection in the paw with I‐BET151, which blocks the interaction of BET proteins with acetylated histones. We assessed the effects of I‐BET151 on acute arthritis and/or inflammatory tissue priming in a model of repeated injections of monosodium urate crystals or zymosan into the mouse paw. I‐BET151 was given before arthritis induction, at peak inflammation, or after healing of the first arthritis bout. We performed transcriptomic (RNA‐Seq), epigenomic (ATAC‐Seq), and functional (invasion, cytokine production, migration, senescence, metabolic flux) analyses of murine and human SFs treated with I‐BET151 in vitro or in vivo. Results Systemic I‐BET151 administration did not affect acute inflammation but abolished inflammatory tissue priming and diminished flare severity in both preventive and therapeutic treatment settings. I‐BET151 was also effective when applied locally in the joint. BET inhibition also inhibited osteoclast differentiation, while macrophage activation in the joint was not affected. Flare reduction after BET inhibition was mediated, at least in part, by rolling back the primed transcriptional, metabolic, and pathogenic phenotype of SFs. Conclusion Inflammatory tissue priming is dependent on transcriptional regulation by BET proteins, making them promising therapeutic targets for prevention of arthritis flares in previously affected joints.
Molecular landscape of immune pressure and escape in aplastic anemia
Authors: Simona Pagliuca, Carmelo Gurnari, Colin Hercus, Sébastien Hergalant, Niroshan Nadarajah, Adam Wahida, Laila Terkawi, Minako Mori, Weiyin Zhou, Valeria Visconte, Stephen Spellman, Shahinaz M. Gadalla, Caiying Zhu, Ping Zhu, Torsten Haferlach, Jaroslaw P. Maciejewski
Journal: Leukemia (2022)
Integrative Functional Genomics Identifies Systemic Lupus Erythematosus Causal Genetic Variant in the <scp><i>IRF5</i></scp> Risk Locus
Authors: Guojun Hou, Tian Zhou, Ning Xu, Zhihua Yin, Xinyi Zhu, Yutong Zhang, Yange Cui, Jianyang Ma, Yuanjia Tang, Zhaorui Cheng, Yiwei Shen, Yashuo Chen, Ling‐Hua Zou, Yong‐fei Wang, Zihang Yin, Ya Guo, Huihua Ding, Zhizhong Ye, Nan Shen
Journal: Arthritis & Rheumatology (2022)

Objective IRF5 plays a crucial role in the development of lupus. Genome‐wide association studies have identified several systemic lupus erythematosus (SLE) risk single‐nucleotide polymorphisms (SNPs) enriched in the IRF5 locus. However, no comprehensive genome editing–based functional analysis exists to establish a direct link between these variants and altered IRF5 expression, particularly for enhancer variants. This study was undertaken to dissect the regulatory function and mechanisms of SLE IRF5 enhancer risk variants and to explore the utilization of clustered regularly interspaced short palindromic repeat interference (CRISPRi) to regulate the expression of disease risk gene to intervene in the disease. Methods Epigenomic profiles and expression quantitative trait locus analysis were applied to prioritize putative functional variants in the IRF5 locus. CRISPR‐mediated deletion, activation, and interference were performed to investigate the genetic function of rs4728142. Allele‐specific chromatin immunoprecipitation–quantitative polymerase chain reaction and allele‐specific formaldehyde‐assisted isolation of regulatory element–quantitative polymerase chain reaction were used to decipher the mechanism of alleles differentially regulating IRF5 expression. The CRISPRi approach was used to evaluate the intervention effect in monocytes from SLE patients. Results SLE risk SNP rs4728142 was located in an enhancer region, indicating a disease‐related regulatory function, and risk allele rs4728142‐A was closely associated with increased IRF5 expression. We demonstrated that an rs4728142‐containing region could act as an enhancer to regulate the expression of IRF5 . Moreover, rs4728142 affected the binding affinity of zinc finger and BTB domain–containing protein 3 (ZBTB3), a transcription factor involved in regulation. Furthermore, in monocytes from SLE patients, CRISPR‐based interference with the regulation of this enhancer attenuated the production of disease‐associated cytokines. Conclusion These results demonstrate that the rs4728142‐A allele increases the SLE risk by affecting ZBTB3 binding, chromatin status, and regulating IRF5 expression, establishing a biologic link between genetic variation and lupus pathogenesis.
Seronegative palindromic rheumatism: what are we talking about? Comment on the article by Yang et al
Authors: Raimon Sanmarti, Beatriz Frade‐Sosa, Rosa Morlà, Juan D. Cañete
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
<i>Fusobacterium</i> and Colorectal Cancer: Important Association or Random Coincidence?
Authors: Blake E. Sanders, Guanxi Qiao, Jodi Hirschman, Matthew Meyerson
Journal: Cancer Research (2022)

Abstract The role of the microbiome in human cancer has become an area of intensive research and controversy. Many reports have highlighted the physical association of Fusobacterium with colorectal cancer. This association has provided diagnostic and therapeutic promise but has also given rise to several controversies regarding the influence of Fusobacterium species on human colorectal cancer. Here, we discuss two areas of controversy surrounding this emerging pathogen: the influence of Fusobacterium on colorectal cancer proliferation and the effect of Fusobacterium on the immune microenvironment of colorectal cancer.
A Detouring Experience Not Recommended: Lessons Learned from PF00299804
Authors: Molly Li, Kevin Mok, Tony Mok
Journal: Cancer Research (2022)

Abstract Patients with mutant EGFR positive non–small cell lung cancer (NSCLC) benefit from tyrosine kinase inhibitor (TKI) treatment. However, all patients ultimately develop acquired resistance, half of which are attributed to the EGFR exon 20 T790M mutation. A landmark publication in Cancer Research in 2007 demonstrated improved drug potency and pan-human EGFR (HER) inhibition with PF00299804, a second-generation EGFR TKI. Compared with first-generation EGFR TKI, PF00299804 showed the ability to overcome T790M mutation in vitro and had the potential to improve treatment outcomes of patients with mutant EGFR-positive NSCLC. Here we review the preclinical and clinical development of PF00299804 and reflect on the lessons learned from this detouring experience. See related article by Engelman and colleagues, Cancer Res 2007;67:11924–32.
A Flare Risk Index Informed by Select Immune Mediators in Systemic Lupus Erythematosus
Authors: Melissa E. Munroe, Derek Blankenship, Daniele DeFreese, Mohan Purushothaman, Wade DeJager, Susan Macwana, Joel M. Guthridge, Stan Kamp, Nancy Redinger, Teresa Aberle, Eliza F. Chakravarty, Cristina Arriens, Yanfeng Li, Hu Zeng, Kathleen A. McCarthy‐Fruin, Shirley‐Ann Osei‐Onomahm, Uma Thanarajasingam, Judith A. James, Eldon Jupe
Journal: Arthritis & Rheumatology (2022)

Systemic lupus erythematosus (SLE) is marked by immune dysregulation linked to varied clinical disease activity. Using a unique longitudinal cohort of SLE patients, this study sought to identify optimal immune mediators informing an empirically refined flare risk index (FRI) reflecting altered immunity prior to clinical disease flare.
The Dawn of the Antibody–Drug Conjugates Era: How T-DM1 Reinvented the Future of Chemotherapy for Solid Tumors
Authors: Paolo Tarantino, Sara M. Tolaney
Journal: Cancer Research (2022)

Abstract Delivering targeted chemotherapy through antibody–drug conjugates (ADC) has emerged as an extremely effective therapeutic strategy for multiple types of cancer. The first agent of this class to be established for treating a solid tumor was trastuzumab emtansine (T-DM1), approved in 2013 for the treatment of HER2-positive metastatic breast cancer. Much of the knowledge that led to this approval came from the landmark Cancer Research publication by Lewis Phillips and colleagues in 2008, where they described the in vitro and in vivo efficacy, pharmacokinetics, and toxicity of T-DM1, demonstrating its relevant preclinical activity against HER2-positive breast cancer models. In this article, the authors also explored the use of different linkers to conjugate the cytotoxic payload to the trastuzumab vehicle, demonstrating improved stability, efficacy, and tolerability of the compound when adopting a specific thioether linker. The findings from this work not only set the stage for the clinical development of T-DM1, but also highlighted the modularity of ADCs, with small changes in their components able to dramatically impact their activity and toxicity. This finding would prove key for the development of novel ADCs, several of which are now reshaping the way we treat breast cancer and other cancer types. In this commentary, we discuss the key implications of the work by Phillips and colleagues, putting it in context of the current and anticipated expansion in the use of ADCs to treat cancer. See related article by Phillips et al., Cancer Res 2008;68:9280–90.
Screening DNA aptamers that control the DNA cleavage, homology-directed repair, and transcriptional regulation of the CRISPR-(d)Cas9 system
Authors: Xinbo Huang, Mingxia Wang, Xia Wu, Yanfen Zou, Jinming Xu, Congcong Cao, Qian Ma, Bo Yu, Yuchen Liu, Yaoting Gui
Journal: Molecular Therapy (2022)

Accurate genome editing based on various molecular tools has always been the focus of gene-editing research and the primary goal for therapeutic application. The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system is a well-established gene-editing method that is preferred due to its simplicity and high efficiency. In this study, a group of single-stranded DNA aptamers with high affinity and high specificity for the Cas9 protein were obtained by the systematic evolution of ligands through the exponential enrichment method. Their binding affinity and possible binding domains to the Cas9 protein were analyzed. In addition, we demonstrated the effectiveness of aptamers in regulating dCas9-modulated gene transcription, in terms of both transcriptional activation and repression. Additionally, the aptamers successfully reduced the off-target effect and improved the efficiency of gene homologous recombination repair mediated by CRISPR-Cas9. The findings suggest a potential method to better control precise gene editing and enrich the diversity of modulating tools for the CRISPR-Cas9 system. Accurate genome editing based on various molecular tools has always been the focus of gene-editing research and the primary goal for therapeutic application. The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system is a well-established gene-editing method that is preferred due to its simplicity and high efficiency. In this study, a group of single-stranded DNA aptamers with high affinity and high specificity for the Cas9 protein were obtained by the systematic evolution of ligands through the exponential enrichment method. Their binding affinity and possible binding domains to the Cas9 protein were analyzed. In addition, we demonstrated the effectiveness of aptamers in regulating dCas9-modulated gene transcription, in terms of both transcriptional activation and repression. Additionally, the aptamers successfully reduced the off-target effect and improved the efficiency of gene homologous recombination repair mediated by CRISPR-Cas9. The findings suggest a potential method to better control precise gene editing and enrich the diversity of modulating tools for the CRISPR-Cas9 system.
Ori-Finder 2022: A Comprehensive Web Server for Prediction and Analysis of Bacterial Replication Origins
Authors: Mei-Jing Dong, Hao Luo, Feng Gao
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract The replication of DNA is a complex biological process that is essential for life. Bacterial DNA replication is initiated at genomic loci referred to as replication origins (oriCs). Integrating the Z-curve method, DnaA box distribution, and comparative genomic analysis, we developed a web server to predict bacterial oriCs in 2008 called Ori-Finder, which is helpful to clarify the characteristics of bacterial oriCs. The oriCs of hundreds of sequenced bacterial genomes have been annotated in the genome reports using Ori-Finder and the predicted results have been deposited in DoriC, a manually curated database of oriCs. This has facilitated large-scale data mining of functional elements in oriCs and strand-biased analysis. Here, we describe Ori-Finder 2022 with updated prediction framework, interactive visualization module, new analysis module, and user-friendly interface. More species-specific indicator genes and functional elements of oriCs are integrated into the updated framework, which has also been redesigned to predict oriCs in draft genomes. The interactive visualization module displays more genomic information related to oriCs and their functional elements. The analysis module includes regulatory protein annotation, repeat sequence discovery, homologous oriC search, and strand-biased analyses. The redesigned interface provides additional customization options for oriC prediction. Ori-Finder 2022 is freely available at http://tubic.tju.edu.cn/Ori-Finder/ and https://tubic.org/Ori-Finder/.
Clinical Images: Impending cardiac tamponade and coated aorta in <scp>Erdheim‐Chester</scp> disease
Authors: Sho Fukui, Satoshi Kobayashi, Mitsumasa Kishimoto
Journal: Arthritis & Rheumatology (2022)

Disclosureform Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Cell-derived nanovesicle-mediated drug delivery to the brain: Principles and strategies for vesicle engineering
Authors: Yujie Liang, Zoya Iqbal, Jianping Lu, Jianhong Wang, Hao Zhang, Xi Chen, Li Duan, Jiang Xia
Journal: Molecular Therapy (2022)

Developing strategies toward safe and effective drug delivery into the central nervous system (CNS) with improved targeting abilities and reduced off-target effects is crucial. CNS-targeted drug carriers made of synthetic molecules raise concerns about their biodegradation, clearance, immune responses, and neurotoxicity. Cell-derived nanovesicles (CDNs) have recently been applied in CNS-targeted drug delivery, because of their intrinsic stability, biocompatibility, inherent homing capability, and the ability to penetrate through biological barriers, including the blood-brain barrier. Among these CDNs, extracellular vesicles and exosomes are the most studied because their surface can be engineered and modified to cater to brain targeting. In this review, we focus on the application of CDNs in brain-targeted drug delivery to treat neurological diseases. We cover recently developed methods of exosome derivation and engineering, including exosome-like particles, hybrid exosomes, exosome-associated adeno-associated viruses, and envelope protein nanocages. Finally, we discuss the limitations and project the future development of the CDN-based brain-targeted delivery systems, and conclude that engineered CDNs hold great potential in the treatment of neurological diseases.
IL-1Ra gene transfer potentiates BMP2-mediated bone healing by redirecting osteogenesis toward endochondral ossification
Authors: Joseph A. Panos, Michael J. Coenen, Christopher V. Nagelli, Erin B. McGlinch, Aysegul Atasoy-Zeybek, Consuelo Lopez De Padilla, Ryan F. Coghlan, Brian Johnstone, Elisabeth Ferreira, Ryan M. Porter, Rodolfo E. De la Vega, Christopher H. Evans
Journal: Molecular Therapy (2022)

An estimated 100,000 patients each year in the United States suffer severe disability from bone defects that fail to heal, a condition where bone-regenerative therapies could provide substantial clinical benefits. Although recombinant human bone morphogenetic protein-2 (rhBMP2) is an osteogenic growth factor that is clinically approved for this purpose, it is only effective when used at exceedingly high doses that incur substantial costs, induce severe inflammation, produce adverse side effects, and form morphologically abnormal bone. Using a validated rat femoral segmental defect model, we show that bone formed in response to clinically relevant doses of rhBMP2 is accompanied by elevated expression of interleukin-1 (IL-1). Local delivery of cDNA encoding the IL-1 receptor antagonist (IL-1Ra) achieved bridging of segmental, critical size defects in bone with a 90% lower dose of rhBMP2. Unlike use of high-dose rhBMP2, bone formation in the presence of IL-1Ra occurred via the native process of endochondral ossification, resulting in improved quality without sacrificing the mechanical properties of the regenerated bone. Our results demonstrate that local immunomodulation may permit effective use of growth factors at lower doses to recapitulate more precisely the native biology of healing, leading to higher-quality tissue regeneration.
HCP5 prevents ubiquitination-mediated UTP3 degradation to inhibit apoptosis by activating c-Myc transcriptional activity
Authors: Yabing Nan, Qingyu Luo, Xiaowei Wu, Wan Chang, Pengfei Zhao, Shi Liu, Zhihua Liu
Journal: Molecular Therapy (2022)

Inducing cancer cell apoptosis through cytotoxic reagents is the main therapeutic strategy for diverse cancer types. However, several antiapoptotic factors impede curative cancer therapy by driving cancer cells to resist cytotoxic agent-induced apoptosis, thus leading to refractoriness and relapse. To define critical antiapoptotic factors that contribute to chemoresistance in esophageal squamous cell carcinoma (ESCC), we generated two pairs of parental and apoptosis-resistant cell models through cisplatin (DDP) induction and then performed whole-transcriptome sequencing. We identified the long noncoding RNA (lncRNA) histocompatibility leukocyte antigen complex P5 (HCP5) as the chief culprit for chemoresistance. Mechanistically, HCP5 interacts with UTP3 small subunit processome component (UTP3) and prevents UTP3 degradation from E3 ligase tripartite motif containing 29 (TRIM29)-mediated ubiquitination. UTP3 then recruits c-Myc to activate vesicle-associated membrane protein 3 (VAMP3) expression. Activated VAMP3 suppresses caspase-dependent apoptosis and eventually leads to chemoresistance. Accordingly, the expression level of the HCP5/UTP3/c-Myc/VAMP3 axis in chemoresistant patients is significantly higher than that in chemosensitive patients. Thus, our study demonstrated that the HCP5/UTP3/c-Myc/VAMP3 axis plays an important role in the inhibition of cancer cell apoptosis and that HCP5 may be a promising chemosensitivity target for cancer treatment. Inducing cancer cell apoptosis through cytotoxic reagents is the main therapeutic strategy for diverse cancer types. However, several antiapoptotic factors impede curative cancer therapy by driving cancer cells to resist cytotoxic agent-induced apoptosis, thus leading to refractoriness and relapse. To define critical antiapoptotic factors that contribute to chemoresistance in esophageal squamous cell carcinoma (ESCC), we generated two pairs of parental and apoptosis-resistant cell models through cisplatin (DDP) induction and then performed whole-transcriptome sequencing. We identified the long noncoding RNA (lncRNA) histocompatibility leukocyte antigen complex P5 (HCP5) as the chief culprit for chemoresistance. Mechanistically, HCP5 interacts with UTP3 small subunit processome component (UTP3) and prevents UTP3 degradation from E3 ligase tripartite motif containing 29 (TRIM29)-mediated ubiquitination. UTP3 then recruits c-Myc to activate vesicle-associated membrane protein 3 (VAMP3) expression. Activated VAMP3 suppresses caspase-dependent apoptosis and eventually leads to chemoresistance. Accordingly, the expression level of the HCP5/UTP3/c-Myc/VAMP3 axis in chemoresistant patients is significantly higher than that in chemosensitive patients. Thus, our study demonstrated that the HCP5/UTP3/c-Myc/VAMP3 axis plays an important role in the inhibition of cancer cell apoptosis and that HCP5 may be a promising chemosensitivity target for cancer treatment.
Serum neutralization of SARS coronavirus 2 Omicron sublineages BA.1 and BA.2 and cellular immune responses 3 months after booster vaccination
Authors: Enagnon Kazali Alidjinou, Julie Demaret, Bénédicte Corroyer-Simovic, Fanny Vuotto, Sophie Miczek, Julien Labreuche, Anne Goffard, Jacques Trauet, Daniela Lupau, Arnaud Dendooven, Dominique Huvent-Grelle, Juliette Podvin, Daniel Dreuil, Karine Faure, Dominique Deplanque, Laurence Bocket, Alain Duhamel, Annie Sobaszek, Didier Hober, Michael Hisbergues, Francois Puisieux, Brigitte Autran, Yazdan Yazdanpanah, Myriam Labalette, Guillaume Lefèvre
Journal: Clinical Microbiology and Infection (2022)
The single cell transcriptional landscape of esophageal adenocarcinoma and its modulation by neoadjuvant chemotherapy
Authors: Wayne Croft, Richard P. T. Evans, Hayden Pearce, Mona Elshafie, Ewen A. Griffiths, Paul Moss
Journal: Molecular Cancer (2022)

Abstract Immune checkpoint blockade has recently proven effective in subsets of patients with esophageal adenocarcinoma (EAC) but little is known regarding the EAC immune microenvironment. We determined the single cell transcriptional profile of EAC in 8 patients who were treatment-naive ( n = 4) or had received neoadjuvant chemotherapy ( n = 4). Analysis of 52,387 cells revealed 10 major cell subsets of tumor, immune and stromal cells. Prior to chemotherapy tumors were heavy infiltrated by T regulatory cells and exhausted effector T cells whilst plasmacytoid dendritic cells were markedly expanded. Two dominant cancer-associated fibroblast populations were also observed whilst endothelial populations were suppressed. Pathological remission following chemotherapy associated with broad reversal of immune abnormalities together with fibroblast transition and an increase in endothelial cells whilst a chemoresistant epithelial stem cell population correlated with poor response. These findings reveal features that underlie and limit the response to current immunotherapy and identify a range of novel opportunities for targeted therapy.
Soluble guanylate cyclase stimulators in patients with heart failure with reduced ejection fraction across the risk spectrum
Authors: Javed Butler, Muhammad Shariq Usman, Kevin J. Anstrom, Robert O. Blaustein, Marc P. Bonaca, Justin A. Ezekowitz, Cecilia Freitas, Carolyn S.P. Lam, Eldrin F. Lewis, JoAnn Lindenfeld, Ciaran J. McMullan, Robert J. Mentz, Christopher O'Connor, Giuseppe M.C. Rosano, Clara Inés Saldarriaga, Michele Senni, James Udelson, Adriaan A. Voors, Faiez Zannad
Journal: European Journal of Heart Failure (2022)